General Population Controls Research Articles

Time-Dependent Analysis of Risk of New-Onset Heart Failure Among Patients With Polymyositis and Dermatomyositis.

To determine the risk and time trends of heart failure (HF) leading to hospitalization in individuals newly diagnosed as having polymyositis/dermatomyositis (PM/DM) relative to non-PM/DM controls at the general population level. A retrospective cohort study was conducted using data from a nationwide insurance database in Taiwan. Patients with incident PM/DM and without a history of HF were selected between 2000 and 2013. Unmatched and propensity score-matched cohorts were established separately. A multivariable Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (HR) for the risk of HF in the unmatched cohort. In the propensity score-matched cohort, general population controls were selected and matched at a 1:1 ratio to the patients with PM/DM based on propensity scores, which accounted for the confounding factors of age, sex, index date (year) of first diagnosis, comorbidities, and medication usage. The cumulative incidence of HF was estimated using the Kaplan-Meier method. A stratified Cox proportional hazards model was used to calculate the HR for the risk of HF events at different follow-up time points among patients with PM/DM compared with non-PM/DM controls in the propensity score-matched cohort. In the unmatched cohort, the study assessed 2,025 patients with PM/DM and 196,109 general population controls. Results of multivariable Cox regression analysis, adjusted for age, sex, comorbidities, and medication usage, revealed a greater risk of HF leading to hospitalization in the PM/DM group than in the control group (adjusted HR 3.29, 95% confidence interval [95% CI] 2.60-4.18). After matching based on propensity score, a total of 1,997 pairs of PM/DM patients and general population controls were identified. In this propensity score-matched cohort, the cumulative incidence of HF in patients with PM/DM at 3 years, 5 years, and 10 years was 3.3%, 4.4%, and 7.4%, respectively. The absolute difference in HF risk in the PM/DM group compared with the control group was 1.8% at 3 years, 2.1% at 5 years, and 3.0% at 10 years. Compared with general population controls, patients with PM/DM exhibited an augmented risk of HF (HR 2.06, 95% CI 1.36-3.12). Analyses stratified according to follow-up time point revealed that the increased risk of HF persisted for up to 10 years after the PM/DM diagnosis. These results indicate that the risk of HF leading to hospitalization was increased in patients with PM/DM throughout the study period, supporting the need for greater vigilance in the monitoring of patients with PM/DM for the development of this potentially lethal complication.

650 Quality of life of patients with end stage heart failure treated with left ventricular assist devices

Abstract Aims Nowadays continuous flow left ventricular assist devices (LVAD) have become a reality for patients with end-stage heart failure (HF) who are failing maximal medical treatment, both eligible or not for heart transplantation. LVADs have demonstrated to improve functional capacity and clinical outcomes, including breathing and activity tolerance, but the impact on patients quality of life (QoL) is still a vexed and open question. Moreover, the device implantation actually requires significant life style changes, high motivation and adherence to treatment, both for patients and their caregivers. Patients must learn to live with the device and to interface with the controller and batteries system, adjusting everyday life’s activities to the device presence. The purpose of our study is to evaluate how the implantation of HeartMate 3™ impact on patients-related QoL and clinical outcomes, compared with general population and other chronic diseases. Methods and results Eight patients (pts) with a diagnosis of end-stage HF were implanted with the HeartMate 3™ LVAD from May 2017 to October 2019 in the Cardiac Surgery Unit of Brotzu Hospital. During a follow-up visit (28.7 ± 11.9 months after surgery), the 7 pts presenting were assessed with two questionnaires, the SF-12 and EuroQoL-5D, in order to evaluate improvement of quality of life compared with clinical presentation. Afterwards we compared the average SF-12 total result with 28 controls from general population and with other important chronic diseases. The analysis of SF-12 questionnaires showed an average of 28.00 ± 8.98 (VN: 12–47) as total score, 11.7 ± 3.4 (VN: 6–20) as physical health component score and 16.2 ± 6.5 (VN: 6–27) as mental health component score. These findings, though within the range of ‘normality’, are closer to the lower scores and show the negative impact of LVAD in everyday patients-related quality of life. Comparing the NYHA functional class with these results, we found a statistically significant negative linear correlation for both total (−0.80, P = 0.03) and mental health component scores (−0.75, P = 0.049). Average total score of our pts significatively differs compared with 28 controls of general population (28.00 ± 8.98 vs. 38.64 ± 6.80, P = 0.014), as well as compared with other chronic diseases like Wilson’s disease (P < 0.001), celiac disease (P < 0.001), obsessive-compulsive disorder (P < 0.001), panic disorder (P < 0.001), major depressive disorder (P = 0.009), multiple sclerosis (P < 0.011), food disorders (P = 0.023), and carotid atherosclerosis (P = 0.049). The EuroQoL-5D questionnaire investigates five particular ‘dimensions’ of the subjectively perceived health-related quality of life (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and shows similar. We found a poor average score at Visual Analogue Scale (58.5 ± 18.86) and a statistically significant negative linear correlation with NYHA functional class (−0.76, P = 0.046). The 42.86% referred no pain or discomfort and in the other four dimensions most of them reported ‘moderate limitations’, both physical or mental, especially for self-care domain (85.71%), as inevitable result of the device’s size. Conclusions LVAD can improve clinical outcomes and functional capacity of carefully select pts with end-stage HF, but the complications encountered during mechanical support and the lifestyle changes required can affect negatively patients well-being. Many studies have shown that most patients experience significant improvement even in QoL’s perception but for others the device have a negative impact on many aspects of normal daily living as well as emotional, mental and social functioning. Our study confirms this conflicting results: physical related-quality of life improves after LVAD implantation but emotional and psychological distress may persist, especially during long-term support, as a result of complications, co-morbidities and personal’s attitudes, values and way of life.

Validation of algorithms for identifying outpatient infections in MS patients using electronic medical records

Background Our multiple sclerosis (MS) stakeholder groups expressed concerns about whether MS disease-modifying therapies (DMTs) increase the risk of specific outpatient infections. Validated methods for identifying the risk of these selected outpatient infections in the general population either do not exist, exclude the clinically important possibility of recurrent infections, or are inaccurate, largely because existing studies relied primarily on International Classification of Diseases (ICD) codes to identify infectious outcomes. Additionally, no studies have validated methods among the MS population, where some MS symptoms can be mistaken for infections (e.g., urinary tract infections (UTIs)).Objective To utilize multiple data elements in the electronic health record (EHR) to improve accurate identification of selected outpatient infections in an MS cohort and general population controls.Methods We searched Kaiser Permanente Southern California's EHR based on ICD-9/10 codes for specified outpatient infections from 1/1/2008-12/31/2018 among our MS cohort (n=6000) and 5:1 general population controls matched on age, sex, and race/ethnicity (n=30,010). Random sample chart abstractions from each group were used to identify common coding errors for outpatient pneumonia, upper and lower respiratory tract infection, UTIs, herpetic infections (herpes zoster (HZ), herpes simplex virus (HSV)), fungal infections, otitis media, cellulitis, and influenza. This information was used to define discrete infectious episodes and to identify the algorithm with the highest positive predictive value (PPV) after supplementing the ICD-coded episodes with radiology, laboratory and/or pharmacy data.Results PPVs relying on ICD codes alone were inaccurate, particularly for identifying recurrent herpetic infections (HZ (42%) and HSV (60%)), UTIs (42%) and outpatient pneumonia (20%) in MS patients. Defining and validating episodes improved the PPVs for all the selected infections. The final algorithms’ PPVs were 80-100% in MS and 75-100% in the general population, after including dispensed treatments (UTI, herpetic infections and yeast vaginitis), timing of dispensed treatments (UTI, herpetic infections and yeast vaginitis), removal of prophylactic antiviral use (herpetic infections), and inclusion of selected laboratory (UTIs) and imaging results (pneumonia). The only exception was outpatient pneumonia, where PPVs improved but remained ≤70%. There were no significant differences in the PPVs for the final algorithms between the MS and general population.Conclusions Provided herein are accurate and validated algorithms that can be used to improve our understanding of how the risk of recurrent outpatient infections are influenced by MS treatments, MS-related disability, and co-morbidities. Findings from such studies will be important in helping patients and clinicians engage in shared decision-making and in developing strategies to mitigate risks of recurrent infections.

The Epidemiology and Burden of Childhood Chronic Pancreatitis in South Australia

To assess longitudinal, population-based data on the prevalence and impact of chronic pancreatitis in children. Administrative data linkage was used to ascertain an index cohort consisting of all individuals who had an initial diagnosis of chronic pancreatitis before age 19years in the South Australian public hospital system between June 2000 and June 2019. Age- and sex-matched controls were drawn from the general population of South Australia, children with type 1 diabetes, and children with type 2 diabetes. Main outcomes and measures included hospital visits, days in hospital, emergency department (ED) visits, intensive care unit (ICU) admissions, education comparators, and incidence and prevalence estimates. A total of 73 incident cases were identified. The crude prevalence and incidence of pediatric chronic pancreatitis were estimated at 6.8/100 000 and 0.98/100 000 per year, respectively. Of the index cohort, 24 cases (32.8%) of pediatric chronic pancreatitis were identified as occurring in children of Aboriginal and/or Torres Strait Islander descent. Compared with matched general population controls, children with chronic pancreatitis averaged 11-fold more hospital visits, 5-fold more ED visits, and 9-fold more ICU admissions; spent 10-fold more days in the hospital; and had a 2-fold higher rate of absence from school (P<.001 for all). Similarly, children with chronic pancreatitis used substantially more health resources than children with type 1 or 2 diabetes. Pediatric patients with chronic pancreatitis consume a high volume of public health services and are significantly impacted in their ability to engage in education.

Gestational Diabetes Mellitus Risk in Pregnant Women With Systemic Lupus Erythematosus.

To investigate the risk of gestational diabetes mellitus (GDM) associated with systemic lupus erythematosus (SLE) by comparing pregnancies in women with SLE to general population controls. We identified singleton pregnancies among women with SLE and general population controls in the Swedish Medical Birth Register (MBR; 2006-2016), sampled from the population-based Swedish Lupus Linkage (SLINK) cohort (1987-2012). SLE was defined by ≥ 2 International Classification of Diseases (ICD)-coded visits in the National Patient Register (NPR) and MBR, with ≥ 1 visit before pregnancy. GDM was defined by ≥ 1 ICD-coded visit in the NPR or MBR. Glucocorticoid (GC) and hydroxychloroquine (HCQ) dispensations within 6 months before and during pregnancy were identified in the Prescribed Drug Register. Risk ratios (RRs) and 95% CIs of GDM associated with SLE were estimated using modified Poisson regression models, stratified by parity and adjusted for maternal age at delivery, year of birth, and obesity. We identified 695 SLE pregnancies including 18 (2.6%) with GDM and 4644 non-SLE pregnancies including 65 (1.4%) with GDM. Adjusted RRs of GDM associated with SLE were 1.11 (95% CI 0.38-3.27) for first deliveries and 2.03 (95% CI 1.21-3.40) for all deliveries. Among SLE pregnancies, GDM occurred in 7/306 (2.3%) with ≥ 1 GC before and/or during pregnancy, 11/389 (2.8%) without GC, 7/287 (2.4%) with ≥ 1 HCQ before and/or during pregnancy, and in 11/408 (2.7%) without HCQ. When looking at all deliveries, SLE was associated with a 2-fold higher risk of GDM. GDM occurrence did not differ by GC or HCQ.

Risk of severe COVID-19 and mortality in patients with established chronic liver disease: a nationwide matched cohort study

Background and aimsSome, but not all, prior studies have suggested that patients with chronic liver disease are at increased risk of contracting COVID-19 and developing more severe disease. However, nationwide data are lacking from well-phenotyped cohorts with liver histology and comparisons to matched general population controls.MethodsWe conducted a nationwide cohort study of all Swedish adults with chronic liver disease (CLD) confirmed by liver biopsy between 1966 and 2017 (n = 42,320), who were alive on February 1, 2020. CLD cases were matched to ≤ 5 population comparators by age, sex, calendar year and county (n = 182,147). Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 hospitalization and severe COVID-19 (intensive care admission or death due to COVID-19).ResultsBetween February 1 and July 31, 2020, 161 (0.38%) CLD patients and 435 (0.24%) general population controls were hospitalized with COVID-19 (aHR = 1.36, 95% CI = 1.11–1.66), while 65 (0.15%) CLD patients and 191 (0.10%) controls developed severe COVID-19 (aHR = 1.08, 95% CI = 0.79–1.48). Results were similar in patients with CLD due to alcohol use, nonalcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, and other etiologies. Among patients with cirrhosis (n = 2549), the aHRs for COVID-19 hospitalization and for severe COVID-19 were 1.08 (95% CI 0.48–2.40) and 1.23 (95% CI = 0.37–4.04), respectively, compared to controls. Moreover, among all patients diagnosed with COVID-19, the presence of underlying CLD was not associated with increased mortality (aHR = 0.85, 95% CI = 0.61–1.19).ConclusionsIn this nationwide cohort, patients with CLD had a higher risk of hospitalization for COVID-19 compared to the general population, but they did not have an increased risk of developing severe COVID-19.

Understanding the Limitations of the Odds Ratio in a Case-Control Study of the Association Between Breast Cancer and Exposure to Antipsychotic Drugs

Evidence suggests that women with schizophrenia are less likely to be screened for breast cancer, more likely to suffer from breast cancer, and more likely to die of breast cancer than women without schizophrenia or general population controls. Antipsychotic drugs, and especially prolactin-raising antipsychotic drugs, have been suggested to increase the breast cancer risk, but the evidence has so far been inconclusive. Against this background, a recent, large, nationwide, case-control study in Finland examined the odds of previous prolonged exposure to prolactin-raising and prolactin-sparing antipsychotic drugs in women with schizophrenia who were (cases) versus were not (controls) diagnosed with breast cancer. The study found that, relative to < 1 year of antipsychotic exposure, breast cancer was associated with significantly increased odds of previous, prolonged (> 5 years) exposure to prolactin-raising antipsychotics. The associations were not statistically significant for prolactin-sparing antipsychotics. The study is critically examined from the perspective of interpretation of the odds ratio and its limitations in order to help readers understand how to better evaluate and generalize findings in case-control studies. This is necessary because results in case-control studies are often incorrectly interpreted, and the limitations of the odds ratios derived in such studies are often not recognized. It is concluded that the design and findings of the reviewed study could not allow readers to judge whether or not prolactin-sparing antipsychotics are associated with lower breast cancer risk than prolactin-raising antipsychotics. In contexts other than breast cancer risk, adverse consequences associated with prolactin elevation are well known, and avoidance or management of hyperprolactinemia is therefore desirable.

Immunogenicity and safety of the human papillomavirus vaccine in young survivors of cancer in the USA: a single-arm, open-label, phase 2, non-inferiority trial

Young survivors of cancer are at increased risk for cancers that are related to human papillomavirus (HPV), primarily caused by oncogenic HPV types 16 and 18. We aimed to examine the immunogenicity and safety of the three-dose series of HPV vaccine in young survivors of cancer. We conducted an investigator-initiated, phase 2, single-arm, open-label, non-inferiority trial at five National Cancer Institute-designated comprehensive cancer centres in the USA. Eligible participants were survivors of cancer who were HPV vaccine-naive, were aged 9-26 years, in remission, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either quadrivalent HPV vaccine (HPV4; enrolments on or before March 1, 2016) or nonavalent HPV vaccine (HPV9; enrolments after March 1, 2016) over 6 months (on day 1, at month 2, and at month 6). We also obtained data from published clinical trials assessing safety and immunogenicity of HPV4 and HPV9 in 9-26-year-olds from the general population, as a comparator group. The primary endpoint was antibody response against HPV types 16 and 18 at month 7 in the per-protocol population. A response was deemed non-inferior if the lower bound of the multiplicity-adjusted 95% CI was greater than 0·5 for the ratio of anti-HPV-16 and anti-HPV-18 geometric mean titres (GMTs) in survivors of cancer versus the general population. Responses were examined separately in male and female participants by age group (ie, 9-15 years and 16-26 years). Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This trial is now completed. Between Feb 18, 2013, and June 22, 2018, we enrolled 453 survivors of cancer, of whom 436 received one or more vaccine doses: 203 (47%) participants had survived leukaemia, 185 (42%) were female, and 280 (64%) were non-Hispanic white. Mean age at first dose was 15·6 years (SD 4·6). 378 (83%) of 453 participants had evaluable immunogenicity data; main reasons for exclusion from per-protocol analysis were to loss to follow-up, patient reasons, and medical reasons. Data were also obtained from 26 486 general population controls. The ratio of mean GMT for anti-HPV types 16 and 18 in survivors of cancer versus the general population was more than 1 for all subgroups (ie, aged 9-15 years, aged 16-26 years, male, and female groups) in both vaccine cohorts (ranging from 1·64 [95% CI 1·12-2·18] for anti-HPV type 16 in female participants aged 9-15 years who received HPV9, to 4·77 [2·48-7·18] for anti-HPV type 18 in male participants aged 16-26 years who received HPV4). Non-inferiority criteria were met within each age and sex subgroup, except against HPV type 18 in female participants aged 16-26 years receiving HPV9 (4·30 [0·00-9·05]). Adverse events were reported by 237 (54%) of 435 participants; injection site pain was most common (174 [40%] participants). One serious adverse event (ie, erythema nodosum) was possibly related to vaccine (HPV9; 16-26 year female cohort). Immunogenicity and safety of HPV vaccine three-dose series in survivors of cancer is similar to that in the general population, providing evidence for use in this clinically vulnerable population. US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities.

Rates and Predictors of Visits to Primary Care Physicians during and after Treatment of Childhood Acute Lymphoblastic Leukemia: A Population-Based Cohort Study

Introduction: Though ideal models of survivorship care are not definitively established, it has been suggested that childhood acute lymphoblastic leukemia (ALL) survivors can be cared for by properly informed primary care physicians (PCP - e.g. family physicians, community pediatricians) given low risks of late effects. PCP-driven models of care are dependent on the willingness of families to re-engage with their PCPs after a prolonged period of treatment delivered by pediatric oncologists during which PCP involvement may be minimal. We thus aimed to identify rates and predictors of PCP visits both during and after treatment among a population-based cohort of children with ALL.Methods: We identified all children <18 years at diagnosis of ALL at a pediatric center in Ontario, Canada between 2002-2012. Patients were linked to healthcare data and matched to population-controls by age, sex, and geography (1:5 ratio). PCP physicians at the time of diagnosis were identified through validated algorithms using primary care billing codes and patient rosters. PCP visit rates during treatment were determined and compared between cases and controls, with cases censored at the time of relapse, stem cell transplant, or death. Post-treatment PCP visit rates were calculated among those completing frontline therapy until relapse, death, or the end of the study period. Predictors included demographic- (e.g. age, sex, socioeconomic status, distance from treatment center), disease-related (e.g. risk status, lineage), and PCP-related variables (e.g. pediatrician vs. non-pediatrician).Results: Of 801 children with ALL, 751 (93.8%) had an identified PCP at the time of diagnosis. Excluding a further 8 (1.0%) patients who did not have treatment information available resulted in 743 cases and 3,112 controls. The median age of children with ALL was 4.0 years [interquartile range (IQR) 3.0-8.0], 409 (55%) of whom were male. Nearly half of patients (361, 48.6%) did not visit their PCP during treatment. The rate of PCP visits during treatment was 0.64 per person per year (PPPY) compared to 1.4 PPPY among controls. Adjusting for age, sex, and socioeconomic status resulted in an adjusted rate ratio (aRR) of 0.47 [95th confidence interval (95CI) 0.40-0.54; p<0.0001]. In multivariable analyses, no disease-related factors were associated with PCP visit rates. Infants had lower PCP visit rates during treatment (RR 0.09 vs. age 1-4 years, 95CI 0.01-0.6, p=0.01) while patients living at greatest distance from their treatment centre had higher rates (RR 1.6, 95CI 1.1-2.3, p=0.01). PCP type (pediatrician vs. other) did not have an impact on visit rates during treatment.Excluding 32 (4.3%) patients who relapsed, died, or underwent stem cell transplant prior to completing frontline therapy yielded 711 cases (survivors) and 2,973 controls available for analyses of post-treatment PCP visits. The median time of follow up after the end of treatment among survivors was 6.0 years (IQR 4.0-8.5). Though 287 (40.4%) of survivors did not visit their PCP during the post-treatment period, survivors overall still experienced greater post-treatment PCP visit rates compared to controls (aRR 1.4, 95CI 1.2-1.6; p<0.0001). This was true throughout the post treatment period, with the greatest increase in visit rates compared to controls seen 10 years from the end of treatment and beyond (aRR 3.6, 95CI 1.7-7.5, p=0.0007). In multivariable analyses, survivors who had seen their PCP during active treatment had post-treatment visit rates twice as high as those who had not (aRR 2.0, 95CI 1.6-2.5; p<0.0001). Survivors with pediatricians as PCPs also had higher post-treatment visit rates compared to survivors who did not (aRR 1.4, 95CI 1.1-1.8; p=0.003).Conclusions: Only a portion of children with ALL see their PCPs during treatment and return to PCP care following the completion of leukemia treatment, indicating that PCP-led survivorship care is feasible only for a subset of this population. The rate of PCP visits among survivors however continues to increase relative to general-population controls beyond 10 years after end of treatment. Post-treatment engagement with PCPs may be improved by PCP involvement during treatment, as well as in some cases the involvement of community pediatricians. DisclosuresGupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Mortality of inactive hepatitis B virus carriers in Japan is similar to that of the general population.

Data on the long-term outcomes of individuals with hepatitis B virus (HBV) infection who are hepatitis envelope antigen (HBeAg)-negative inactive carriers (ICs) are limited due to small numbers. We compared the long-term prognosis of well-defined ICs with that of age- and gender-matched general population controls. A total of 526 HBeAg-negative patients who demonstrated alanine aminotransferase (ALT) level ≤40U/L and HBV DNA level ≤4.3 log IU/ml at least three times within 1year after the start of follow-up were enrolled as ICs. Inactive carriers were divided into two groups: Group A (n=332), whose ALT level was ≤30U/L and HBV DNA level was ≤3.3 log IU/ml, and Group B (remaining patients, n=194). We determined the long-term prognosis of ICs and compared it with that of general population controls. We also analyzed factors associated with hepatitis B surface antigen (HBsAg) clearance and phase transition in ICs. There were no significant differences in hepatocellular carcinoma development or all-cause, liver-related, or non-liver-related mortality between Groups A and B. There was no significant difference in all-cause mortality between ICs and the general population. Low HBsAg level (≤3.0 log IU/ml) and the presence of fatty liver were associated with HBsAg clearance and high alpha-fetoprotein level was associated with phase transition. The long-term prognosis of well-defined ICs was similar to that of general population controls. In addition, the ICs had a high HBsAg clearance rate and low phase transition rate.

Prevalence of mental disorders in patients with cancer compared to matched controls – secondary analysis of two nationally representative surveys

Aim To compare prevalence rates of mental disorders in patients with cancer and general population controls. Method In two stratified nationally representative surveys, the 12-month prevalence of mental disorders was assessed in 2141 patients with cancer and 4883 general population controls by the standardized Composite International Diagnostic Interview (CIDI). We determined odds ratios (ORs) to compare the odds for mental disorders (combined and subtypes) in cancer patients with age- and gender-matched controls. Results The 12-month prevalences rate for any mental disorder was significantly higher in patients with cancer compared to controls (OR 1.28, 95% CI 1.14–1.45). Prevalence rates were at least two times higher for unipolar mood disorders (major depression: OR 2.07, 95% CI 1.71–2.51; dysthymia: OR 2.93, 95% CI 2.13–4.02) and mental disorders due to a general medical condition (OR 3.31, 95% CI 2.32–4.71). There was no significant elevation for anxiety disorders overall (OR 0.95, 95% CI 0.81–1.11). Mildly elevated prevalence rates emerged for post-traumatic stress disorder (OR 1.57, 95% CI 1.11–2.23) and social phobia (OR 1.57, 95% CI 1.07–2.31), while specific phobia (OR 0.82, 95% CI 0.67–1.00) and agoraphobia (OR 0.49, 95% CI 0.33–0.73) were significantly less frequent in cancer. Conclusions While elevated depression rates reinforce the need for its systematic diagnosis and treatment, lower prevalences were unexpected given previous evidence. Whether realistic illness-related fears and worries contribute to lower occurrence of anxiety disorders with excessive fears in cancer may be of interest to future research.

Characterizing Differences in Thymic Function in Women With and Without Vulvodynia: A Community-Based Study.

The aim of the study was to evaluate the association between vulvodynia and thymic function. In this case-control study of 200 clinically confirmed cases of vulvodynia and 205 general population controls residing in the Minneapolis/Saint Paul metropolitan area, we used DNA extracted from whole blood to measure levels of signal joint T-cell receptor excision circles (sjTRECs), a measure of thymic output. We used logistic regression to evaluate the association between vulvodynia and thymic function. In 405 participants (aged 18-40 years), we observed an association between decreasing thymic function and increasing age. Women with vulvodynia had a steeper decline in sjTREC values across age categories compared with women without vulvodynia. In addition, at younger ages, women with vulvodynia had higher sjTREC values compared with women without vulvodynia. In older women, those with vulvodynia had lower sjTREC than those without vulvodynia. When accounting for recency of vulvar pain onset, women with a shorter time since pain onset had higher thymic function compared with women with a longer time since vulvar pain onset. These findings suggest that at younger ages, women with vulvodynia have higher thymic output and a more precipitous decline of thymic function than those without vulvodynia. It also seems that a strong immune inflammatory response is present proximate to the onset of vulvar pain and may wane subsequently over time.

Mast cell activation symptoms are prevalent in Long-COVID

ObjectivesHyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC. MethodsAdults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms. ResultsThere were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. ConclusionsMCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.

Cancer Risk in Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study.

Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity. We conducted a population-based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N=8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N=39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person-years [PYs]; difference=2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18-1.36]), driven primarily by HCC (difference=1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56-25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; Ptrend <0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences=0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers. Compared with controls, patients with biopsy-proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.

Prenatal exposure to mixtures of endocrine-disrupting chemicals and autism spectrum disorder

BACKGROUND AND AIM: Mixtures methods have the potential to address the unclear relationship between prenatal exposure to endocrine-disrupting chemicals (EDCs) and risk of autism spectrum disorder (ASD). However, mixtures studies in this area are currently sparse. This study examines the relationship of prenatal exposure to a mixture of 25 EDCs, representing 4 classes of persistent pollutants, and ASD. METHODS: We analyzed data from the Early Markers for Autism (EMA) Study, a population-based, case-control study of children born during 2000-2003 in Southern California. Children diagnosed with ASD (n=491) were identified from clinical records of the Department of Developmental Services and were confirmed by expert review. General population (GP) controls (n=373) were randomly sampled from birth certificate files and frequency matched to children with ASD by sex, birth month, and birth year. Eleven polychlorinated biphenyls (PCBs), 6 brominated flame retardants (BFRs), 2 organochlorine pesticides (OCPs), and 6 polyfluoroalkyl substances (PFAS) were detectable in maternal serum samples collected during the second trimester. To examine the relationship between ASD and EDC mixtures, both within each chemical subclass and across all EDCs, we applied two METHODS: weighted quantile sums regression (WQSR) with repeated-holdout validation and Bayesian kernel machine regression (BKMR). RESULTS:In WQSR adjusted for covariates, PCB, PFAS, and BFR mixtures were not associated with ASD when constrained to the positive direction, but BFRs were associated with ASD in the negative direction (aOR: 0.82; 95%CI: 0.71, 0.95 per quartile increase). Results from BKMR were generally consistent with WQSR, with PBDE 153 contributing the most to both BFR mixture models. WQSR and BKMR analyses showed null associations between the aggregate EDC mixture and ASD. BKMR analyses did not indicate interaction between any of the EDC biomarkers. CONCLUSIONS:Results suggest that prenatal exposure to the mixture of these EDCs is not adversely associated with overall ASD risk. KEYWORDS: autism, mixtures, endocrine-disrupting compounds, prenatal

Improving the measurement of alexithymia in autistic adults: a psychometric investigation of the 20-item Toronto Alexithymia Scale and generation of a general alexithymia factor score using item response theory

BackgroundAlexithymia, a personality trait characterized by difficulties interpreting emotional states, is commonly elevated in autistic adults, and a growing body of literature suggests that this trait underlies several cognitive and emotional differences previously attributed to autism. Although questionnaires such as the 20-item Toronto Alexithymia Scale (TAS-20) are frequently used to measure alexithymia in the autistic population, few studies have investigated the psychometric properties of these questionnaires in autistic adults, including whether differential item functioning (I-DIF) exists between autistic and general population adults.MethodsThis study is a revised version of a previous article that was retracted due to copyright concerns (Williams and Gotham in Mol Autism 12:1–40). We conducted an in-depth psychometric analysis of the TAS-20 in a large sample of 743 cognitively able autistic adults recruited from the Simons Foundation SPARK participant pool and 721 general population controls enrolled in a large international psychological study. The factor structure of the TAS-20 was examined using confirmatory factor analysis, and item response theory was used to generate a subset of the items that were strong indicators of a “general alexithymia” factor. Correlations between alexithymia and other clinical outcomes were used to assess the nomological validity of the new alexithymia score in the SPARK sample.ResultsThe TAS-20 did not exhibit adequate model fit in either the autistic or general population samples. Empirically driven item reduction was undertaken, resulting in an 8-item general alexithymia factor score (GAFS-8, with “TAS” no longer referenced due to copyright) with sound psychometric properties and practically ignorable I-DIF between diagnostic groups. Correlational analyses indicated that GAFS-8 scores, as derived from the TAS-20, meaningfully predict autistic trait levels, repetitive behaviors, and depression symptoms, even after controlling for trait neuroticism. The GAFS-8 also presented no meaningful decrement in nomological validity over the full TAS-20 in autistic participants.LimitationsLimitations of the current study include a sample of autistic adults that was majority female, later diagnosed, and well educated; clinical and control groups drawn from different studies with variable measures; only 16 of the TAS-20 items being administered to the non-autistic sample; and an inability to test several other important psychometric characteristics of the GAFS-8, including sensitivity to change and I-DIF across multiple administrations.ConclusionsThese results indicate the potential of the GAFS-8 to robustly measure alexithymia in both autistic and non-autistic adults. A free online score calculator has been created to facilitate the use of norm-referenced GAFS-8 latent trait scores in research applications (available at https://asdmeasures.shinyapps.io/alexithymia).

Occupational Exposures and Smoking in Eosinophilic Granulomatosis With Polyangiitis: A Case-Control Study.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Environmental agents and occupational exposures may confer susceptibility to EGPA, but data are scarce. This study was undertaken to investigate the association between occupational exposures (e.g., silica, farming, asbestos, and organic solvents) and other environmental agents (e.g., smoking) and the risk of EGPA. Patients with newly diagnosed EGPA (n = 111) and general population controls (n = 333) who were matched for age, sex, and geographic area of origin were recruited at a national referral center for EGPA. Exposures were assessed using a dedicated questionnaire administered by a specialist in occupational medicine, under blinded conditions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Exposures to silica (OR 2.79 [95% CI 1.55-5.01], P = 0.001), organic solvents (OR 3.19 [95% CI 1.91-5.34], P < 0.001), and farming (OR 2.71 [95% CI 1.71-4.29], P < 0.001) were associated with an increased risk of EGPA. Co-exposure to silica and farming yielded an OR of 9.12 (95% CI 3.06-27.19, P < 0.001), suggesting a multiplicative effect between these 2 exposures. Smoking (current and former smokers combined) was significantly less frequent among patients with EGPA compared to controls (OR 0.49 [95% CI 0.29-0.70], P < 0.001). The pack-year index was also lower among patients with EGPA (OR 0.96 [95% CI 0.94-0.98], P < 0.001). The association of silica and farming was primarily aligned with ANCA-positive EGPA, while the association of smoking status and organic solvents was primarily aligned with ANCA-negative EGPA. The environment can influence susceptibility to EGPA. Exposure to silica, farming, or organic solvents is associated with an increased risk of EGPA, while smoking is associated with a lower risk. These exposures seem to have distinct effects on different EGPA subsets.

Association of Field Position and Career Length With Risk of Neurodegenerative Disease in Male Former Professional Soccer Players

Neurodegenerative disease mortality is higher among former professional soccer players than general population controls. However, the factors contributing to increased neurodegenerative disease mortality in this population remain uncertain. To investigate the association of field position, professional career length, and playing era with risk of neurodegenerative disease among male former professional soccer players. This cohort study used population-based health record linkage in Scotland to evaluate risk among 7676 male former professional soccer players born between January 1, 1900, and January 1, 1977, and 23 028 general population control individuals matched by year of birth, sex, and area socioeconomic status providing 1 812 722 person-years of follow-up. Scottish Morbidity Record and death certification data were available from January 1, 1981, to December 31, 2016, and prescribing data were available from January 1, 2009, to December 31, 2016. Database interrogation was performed on December 10, 2018, and data were analyzed between April 2020 and May 2021. Participation in men's soccer at a professional level. Outcomes were obtained by individual-level record linkage to national electronic records of mental health and general hospital inpatient and day-case admissions as well as prescribing information and death certification. Risk of neurodegenerative disease was evaluated between former professional soccer players and matched general population control individuals. In this cohort study of 30 704 male individuals, 386 of 7676 former soccer players (5.0%) and 366 of 23 028 matched population control individuals (1.6%) were identified with a neurodegenerative disease diagnosis (hazard ratio [HR], 3.66; 95% CI, 2.88-4.65; P < .001). Compared with the risk among general population control individuals, risk of neurodegenerative disease was highest for defenders (HR, 4.98; 95% CI, 3.18-7.79; P < .001) and lowest for goalkeepers (HR, 1.83; 95% CI, 0.93-3.60; P = .08). Regarding career length, risk was highest among former soccer players with professional career lengths longer than 15 years (HR, 5.20; 95% CI, 3.17-8.51; P < .001). Regarding playing era, risk remained similar for all players born between 1910 and 1969. The differences in risk of neurodegenerative disease observed in this cohort study imply increased risk with exposure to factors more often associated with nongoalkeeper positions, with no evidence this association has changed over the era studied. While investigations to confirm specific factors contributing to increased risk of neurodegenerative disease among professional soccer players are required, strategies directed toward reducing head impact exposure may be advisable in the meantime.

Mapping health-related quality of life after kidney transplantation by group comparisons: a systematic review.

BackgroundHealth-related quality of life (HRQOL) is becoming an increasingly important outcome in kidney transplantation (KT). To describe HRQOL in kidney transplant recipients (KTRs), this systematic review summarizes literature that compared HRQOL among KTRs and other relevant populations [i.e. patients receiving dialysis, patients on the waiting list (WL) for KT, patients with chronic kidney disease (CKD) not receiving renal replacement therapy (RRT), the general population (GP) and healthy controls (HCs)] and themselves before KT.MethodsThe literature search was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Eligible studies published between January 2000 and October 2020 were included.ResultsForty-four studies comprising 6929 KTRs were included in this systematic review. Despite the study heterogeneity, KTRs reported a higher HRQOL after KT compared with pre-transplantation and compared with patients receiving dialysis with or without being on the WL, especially in disease-specific domains (i.e. burden and effects of kidney disease). Additionally, KTRs had similar to marginally higher HRQOL compared with patients with CKD Stages 3–5 not receiving RRT. When compared with HCs or the GP, KTRs reported similar HRQOL in the first 1 or 2 years after KT and lower physical HRQOL and lower to comparable mental HRQOL in studies with longer post-transplant time.ConclusionsThe available evidence suggests that HRQOL improves after KT and can be restored to but not always maintained at pre-CKD HRQOL levels. Future studies investigating intervention targets to improve or maintain post-transplant HRQOL are needed.

Long-term survival after primary intracerebral hemorrhage: A population-based case-control study spanning a quarter of a century.

The aim of this study was to determine the differences in life expectancy and causes of death after primary intracerebral hemorrhage (ICH) relative to general population controls. In a population-based setting, 963 patients from Northern Ostrobothnia who had their first-ever ICH between 1993 and 2008 were compared with a cohort of 2884 sex- and age-matched controls in terms of dates and causes of death as extracted from the Causes of Death Register kept by Statistics Finland and valid up to the end of 2017. Of our 963 patients, 781 died during the follow-up time (mortality 81.1%). Cerebrovascular disease was the most common cause of death for these patients, 37.3% compared with 8.2% amongst the controls. The most common reasons for cerebrovascular mortality in the ICH patients were late sequelae of ICH in 12.8% (controls 0%) and new bleeding in 10.6% (controls 1.0%). The long-term survivors had a smaller ICH volume (median 12ml) than those patients who died within 3months (median 39ml). The mortality rate of ICH patients during a follow-up between 12 and 24years was still higher than that of their controls (hazard ratio 2.08, 95% confidence interval 1.58-2.74, p<0.001). Very long-term ICH survivors have a constant excess mortality relative to controls even 10years after the index event. A significantly larger proportion of patients died of cerebrovascular causes and fewer because of cancer relative to the controls.